ASCO 2020: Study EV-103: Durability Results of Enfortumab Vedotin plus Pembrolizumab for Locally Advanced or Metastatic Urothelial Carcinoma

( The prognosis for patients with locally advanced and metastatic urothelial carcinoma of the bladder is poor. Currently, cisplatin-based chemotherapy is the standard of care for these patients. Immunotherapeutic approaches (utilizing atezolizumab and pembrolizumab) are currently approved as first-line therapy in patients who are ineligible for cisplatin-containing regimes and have PD-L1 expression and those who are ineligible for platinum-containing regimes regardless of PD-L1 status. In the second line setting, a number of other agents are also approved.

In contrast to immunotherapeutic approaches, Enfortumab vedotin is a targeted therapy for the treatment of advanced bladder cancer. Enfortumab vedotin is an antibody-drug conjugate that delivers the microtubule-disrupting agent monomethyl auristatin E (MMAE) to cells expressing Nectin-4, a cell surface protein which is highly expressed in advanced bladder cancer.

Based on the EV-201 trial, Enfortumab vedotin was approved for patients with metastatic bladder cancer who had previously received platinum-containing chemotherapy as first-line therapy and immunotherapy using checkpoint inhibitors as second-line therapy.

The ongoing phase 1b/2 study EV-103/KEYNOTE-869 is designed to assess the safety and antitumor activity of Enfortumab vedotin as monotherapy and in combination with pembrolizumab, with or without chemotherapy in patients with advanced bladder cancer.


Initial data from the EV-103 study were presented by Dr. Hoimes at ESMO 2019 demonstrating the activity of the combination of Enfortumab vedotin in combination with pembrolizumab. In a poster presented at this year’s 2020 American Society of Clinical Oncology Virtual Annual Meeting, Dr. Rosenberg presented an updated analysis of these data assessing the durability of outcomes as well as safety.

While EV-103 is a multi-stage trial with many arms, the present abstract provides the results of treatment with Enfortumab vedotin (1.25mg/kg, administered days 1 and 8 of a 3-week cycle) and pembrolizumab (administered day 1) in the first-line treatment of cisplatin-ineligible patients with advanced bladder cancer. In this dose expansion cohort, the primary outcome was safety and tolerability while secondary objectives included determination of recommended Enfortumab vedotin dose, objective response rate, disease control rate, duration of response, progression-free survival per RECIST v1.1, and overall survival.

With a data cut-off of October 8, 2019, the authors had accrued 45 eligible patients who received a median of 9 cycles (range 1 to 22 cycles) of therapy with Enfortumab vedotin and pembrolizumab. Median age of included patients was 69 years (range 51 to 90 years).

Assessing the primary outcome of safety and tolerability, the authors identified common treatment emergent adverse events including fatigue (58%, 11% ≥grade 3), alopecia (53%), and peripheral sensory neuropathy (53%, 4% ≥grade 3). One patient died of multiple organ failure which was deemed attributable to study treatment.

Moving on to secondary outcomes, over a median follow-up of 11.5 months, confirmed investigator-assessed ORR was 73.3% (95% confidence interval 58.1 to 85.4). Of these 33 patients, 7 (15.6%) achieved a complete response (CR). The disease control rate was 93.3% (42 of 45 patients).

While not statistically tested, objective response rate was similar among patients who had high levels of PD-L1 (11 of 14, 78.6%) and low levels (12 of 19, 63.2%).

Among the 33 patients who had an objective response, 18 (55%) have ongoing responses including 11 with responses beyond 10 months. As a result of these ongoing responses, the median duration of response was not reached (range 1.2 to greater than 12.9 months). The 12-month duration of response rate was 53.7% (95% confidence interval 27.4 to 74.1%).

The median PFS was 12.3 months (95% confidence interval, 7.98 to not reached). While median overall survival was not reached (range 0.66 to greater than 19.2 months), the 12-month overall survival was 81.6% (95% confident interval 62.0 to 91.8%).


In conclusion, the authors demonstrate promising activity from Enfortumab vedotin and pembrolizumab as first-line platinum-sparing therapy in patients with advanced bladder cancer. Ongoing accrual of other cohorts of the EV-103 trial will continue to define the role of Enfortumab vedotin as monotherapy and in combination with pembrolizumab, with or without chemotherapy, in patients with advanced bladder cancer.

Presented by: Jonathan E. Rosenberg, MD, Chief of the Genitourinary Medical Oncology Service, Division of Solid Tumor Oncology; and the Enno W. Ercklentz Chair at Memorial Sloan Kettering Cancer Center, New York City, New York 

Co-Authors: Thomas W. Flaig, Terence W. Friedlander, Matthew I. Milowsky, Sandy Srinivas, Daniel Peter Petrylak, Jaime R. Merchan, Mehmet Asim Bilen, Anne-Sophie Carret, Nancy Yuan, Carolyn Sasse, Christopher J. Hoimes

Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center Contact: @WallisCJD on Twitter at the 2020 ASCO Annual Meeting, Virtual Scientific Program #ASCO20, May 29-31, 2020.

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